tbuckley/cabot-search huggingface dataset:
Safety and Efficacy of Dual TYK2 Inhibitor and Monoclonal Antibody Therapy for Psoriasis and Psoriatic Arthritis
Authors: Sophie Guénin, Elizabeth Andrews, Mark G Lebwohl
Journal: British Journal of Dermatology (2023)

Deucravacitinib may confer an additive effect in some patients with psoriasis and psoriatic arthritis whose disease is not adequately controlled on systemic monotherapy. This study found that deucravacitinib proved to be a safe adjunctive therapy to patients with refractory disease.
New analyses exploring multimorbidity in psoriasis
Authors: Nick Dand, Ravi Ramessur
Journal: British Journal of Dermatology (2023)

Journal Article Accepted manuscript New analyses exploring multimorbidity in psoriasis Get access Nick Dand, Nick Dand Department of Medical and Molecular Genetics, King’s College London, UK Correspondence: Nick Dand Email:nick.dand@kcl.ac.uk https://orcid.org/0000-0002-1805-6278 Search for other works by this author on: Oxford Academic Google Scholar Ravi Ramessur Ravi Ramessur St John’s Institute of Dermatology, King’s College London, UK Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad475, https://doi.org/10.1093/bjd/ljad475 Published: 27 November 2023 Article history Received: 17 November 2023 Accepted: 24 November 2023 Published: 27 November 2023
Diverse macrophage populations contribute to distinct manifestations of human cutaneous graft-versus-host disease
Authors: Johanna Strobl, Laura M Gail, Laura Krecu, Shaista Madad, Lisa Kleissl, Luisa Unterluggauer, Anna Redl, Kveta Brazdilova, Simona Saluzzo, Philipp Wohlfarth, Hanna A Knaus, Margit Mitterbauer, Werner Rabitsch, Muzlifah Haniffa, Georg Stary
Journal: British Journal of Dermatology (2023)

Abstract Background Graft-versus-host disease (GvHD) is a major life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT), limiting the broad application of HSCT for haematological malignancies. Cutaneous GvHD is described as a post-transplant inflammatory reaction by skin-infiltrating donor T cells and remaining recipient tissue-resident memory T cells. Despite the major influence of lymphocytes on GvHD pathogenesis, the complex role of mononuclear phagocytes (MNPs) in tissues affected by GvHD is increasingly appreciated. Objectives To characterize the identity, origin and functions of MNPs in patients with acute cutaneous GvHD. Methods Using single-cell RNA sequencing and multiplex tissue immunofluorescence, we identified an increased abundance of MNPs in skin and blood from 36 patients with acute cutaneous GvHD. In cases of sex-mismatched transplantation, we used expression of X-linked genes to detect rapid tissue adaptation of newly recruited donor MNPs resulting in similar transcriptional states of host- and donor-derived macrophages within GvHD skin lesions. Results We showed that cutaneous GvHD lesions harbour expanded CD163+ tissue-resident macrophage populations with anti-inflammatory and tissue-remodelling properties including interleukin-10 cytokine production. Cell–cell interaction analyses revealed putative signalling to strengthen regulatory T-cell responses. Notably, macrophage polarization in chronic cutaneous GvHD types was proinflammatory and drastically differed from acute GvHD, supporting the notion of distinct cellular players in different clinical GvHD subtypes. Conclusions Overall, our data reveal a surprisingly dynamic role of MNPs after HSCT. Specific and time-resolved targeting to repolarize this cell subset may present a promising therapeutic strategy in combatting GvHD skin inflammation.
Systematic review and meta‐analyses on the accuracy of diagnostic tests for IgE‐mediated food allergy
Authors: Carmen Riggioni, Cristian Ricci, Beatriz Moya, Dominic Wong, Evi van Goor, Irene Bartha, Betul Buyuktiryaki, Mattia Giovannini, Sashini Jayasinghe, Hannah Jaumdally, Andreina Marques‐Mejias, Alexandre Piletta‐Zanin, Anna Berbenyuk, Margarita Andreeva, Daria Levina, Ekaterina Iakovleva, Graham Roberts, Derek Chu, Rachel Peters, George du Toit, Isabel Skypala, Alexandra F. Santos
Journal: Allergy (2023)

Abstract The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta‐analyses to assess the accuracy of diagnostic tests for IgE‐mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta‐analyses were undertaken for food‐test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double‐blind placebo‐controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2‐sIgE had 92%, Cor a 14‐sIgE 95%, Ana o 3‐sIgE 94%, casein‐sIgE 93%, ovomucoid‐sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.
SDF‐1 Bound Heparin Nanoparticles Recruit Progenitor Cells for Their Differentiation and Promotion of Angiogenesis after Stroke
Authors: Katrina L. Wilson, Neica I. Joseph, Lauren A. Onweller, Alexa R. Anderson, Nicole J. Darling, Jennifer David‐Bercholz, Tatiana Segura
Journal: Advanced Healthcare Materials (2023)

Angiogenesis after stroke is correlated with enhanced tissue repair and functional outcomes. The existing body of research in biomaterials for stroke focuses on hydrogels for the delivery of stem cells, growth factors, or small molecules or drugs. Despite the ability of hydrogels to enhance all these delivery methods, no material has significantly regrown vasculature within the translatable timeline of days to weeks after stroke. Here, two novel biomaterial formulations of granular hydrogels are developed for tissue regeneration after stroke: highly porous microgels (i.e., Cryo microgels) and microgels bound with heparin-norbornene nanoparticles with covalently bound SDF-1α. The combination of these materials results in perfused vessels throughout the stroke core in only 10 days, in addition to increased neural progenitor cell recruitment, maintenance, and increased neuronal differentiation.
A phase 2 <scp>open‐label</scp> extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema
Authors: Remy S. Petersen, Laura Bordone, Marc A. Riedl, Raffi Tachdjian, Timothy J. Craig, William R. Lumry, Michael E. Manning, Jonathan A. Bernstein, Jason Raasch, Bruce L. Zuraw, Yiwen Deng, Kenneth B. Newman, Veronica J. Alexander, Cindy Lui, Eugene Schneider, Danny M. Cohn
Journal: Allergy (2023)

Abstract Background Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality‐of‐life (ISIS721744‐CS2, NCT04030598). We report the 2‐year interim analysis of the phase 2 open‐label extension (OLE) study (ISIS 721744‐CS3, NCT04307381). Methods In the OLE, the on‐treatment study period consisted of fixed (weeks 1–13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17–105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment‐emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality‐of‐life assessments. Results Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run‐in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02–0.10; median, 0.04 on‐treatment vs. mean, 2.70/month; 95% CI, 1.94–3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing ( n = 8) was 0.29 (range, 0.0–1.7; 95% CI, −0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D‐dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. Conclusion The 2‐year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.
Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria
Authors: Steven Kho, Nurjati C. Siregar, Labibah Qotrunnada, Aurélie Fricot, Abdoulaye Sissoko, Putu A. I. Shanti, Freis Candrawati, Noy N. Kambuaya, Hasrini Rini, Benediktus Andries, David Hardy, Nur I. Margyaningsih, Fauziyah Fadllan, Desandra A. Rahmayenti, Agatha M. Puspitasari, Amelia R. Aisah, Leo Leonardo, Bagus T. G. Yayang, Dewi S. Margayani, Pak Prayoga, Leily Trianty, Enny Kenangalem, Ric N. Price, Tsin W. Yeo, Gabriela Minigo, Rintis Noviyanti, Jeanne R. Poespoprodjo, Nicholas M. Anstey, Pierre A. Buffet
Journal: American Journal of Hematology (2023)

Abstract Splenomegaly frequently occurs in patients with Plasmodium falciparum (Pf) or P. vivax (Pv) malarial anemia, but mechanisms underlying this co‐occurrence are unclear. In malaria‐endemic Papua, Indonesia, we prospectively analyzed red blood cell (RBC) concentrations in the spleen and spleen‐mimetic retention in 37 subjects splenectomized for trauma or hyperreactive splenomegaly, most of whom were infected with Plasmodium . Splenomegaly (median 357 g [range: 80–1918 g]) was correlated positively with the proportion of red‐pulp on histological sections (median 88.1% [range: 74%–99.4%]; r = .59, p = .0003) and correlated negatively with the proportion of white‐pulp (median 8.3% [range: 0.4%–22.9%]; r = −.50, p = .002). The number of RBC per microscopic field (&gt;95% uninfected) was correlated positively with spleen weight in both Pf‐infected ( r = .73; p = .017) and Pv‐infected spleens ( r = .94; p = .006). The median estimated proportion of total‐body RBCs retained in Pf‐infected spleens was 8.2% (range: 1.0%–33.6%), significantly higher than in Pv‐infected (2.6% [range: 0.6%–23.8%]; p = .015) and PCR‐negative subjects (2.5% [range: 1.0%–3.3%]; p = .006). Retained RBCs accounted for over half of circulating RBC loss seen in Pf infections. The proportion of total‐body RBC retained in Pf‐ and Pv‐infected spleens correlated negatively with hemoglobin concentrations ( r = −.56, p = .0003), hematocrit ( r = −.58, p = .0002), and circulating RBC counts ( r = −.56, p = .0003). Splenic CD71‐positive reticulocyte concentrations correlated with spleen weight in Pf (r = 1.0; p = .003). Retention rates of peripheral and splenic RBCs were correlated negatively with circulating RBC counts ( r = −.69, p = .07 and r = −.83, p = .008, respectively). In conclusion, retention of mostly uninfected RBC in the spleen, leading to marked congestion of the red‐pulp, was associated with splenomegaly and is the major mechanism of anemia in subjects infected with Plasmodium , particularly Pf.
Blood Pressure Effect of Traffic-Related Air Pollution
Authors: Michael T. Young, Karen Jansen, Kristen E. Cosselman, Timothy R. Gould, James A. Stewart, Timothy Larson, Coralynn Sack, Sverre Vedal, Adam A. Szpiro, Joel D. Kaufman
Journal: Annals of Internal Medicine (2023)

Ambient air pollution, including traffic-related air pollution (TRAP), increases cardiovascular disease risk, possibly through vascular alterations. Limited information exists about in-vehicle TRAP exposure and vascular changes.
Progress in RAS‐targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras
Authors: Xinchen Lu, Jinmei Jin, Ye Wu, Xiaoxia Liu, Xiaohui Liang, Jiayi Lin, Qingyan Sun, Jiangjiang Qin, Weidong Zhang, Xin Luan
Journal: Medicinal Research Reviews (2023)

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.
Chimeric Antigen Receptor (CAR) T-Cell Products for Pediatric Cancers: Why Alternative Development Paths Are Needed
Authors: Claudia Rossig, Andrew D. Pearson, Gilles Vassal, Nicole Scobie, Nick Bird, Patricia Blanc, H. Josef Vormoor, Friso G. Calkoen, Franco Locatelli, Francesca del Bufalo, Susana Rives, Elad Jacoby, Adriana Balduzzi, Jean-Pierre Bourquin, André Baruchel
Journal: Journal of Clinical Oncology (2023)
Diabetes and Multiple Long-term Conditions: A Review of Our Current Global Health Challenge
Authors: Kamlesh Khunti, Yogini V. Chudasama, Edward W. Gregg, Monika Kamkuemah, Shivani Misra, Jerry Suls, Nikhil S. Venkateshmurthy, Jonathan Valabhji
Journal: Diabetes Care (2023)

Use of effective treatments and management programs is leading to longer survival of people with diabetes. This, in combination with obesity, is thus contributing to a rise in people living with more than one condition, known as multiple long-term conditions (MLTC or multimorbidity). MLTC is defined as the presence of two or more long-term conditions, with possible combinations of physical, infectious, or mental health conditions, where no one condition is considered as the index. These include a range of conditions such as cardiovascular diseases, cancer, chronic kidney disease, arthritis, depression, dementia, and severe mental health illnesses. MLTC has major implications for the individual such as poor quality of life, worse health outcomes, fragmented care, polypharmacy, poor treatment adherence, mortality, and a significant impact on health care services. MLTC is a challenge, where interventions for prevention and management are lacking a robust evidence base. The key research directions for diabetes and MLTC from a global perspective include system delivery and care coordination, lifestyle interventions and therapeutic interventions.
Venetoclax plus hypomethylating agents in newly diagnosed acute myeloid leukemia patients with RUNX1::RUNX1T1: a retrospective propensity score matching study
Authors: Miao Wang, Han-Yu Cao, Kai-Wen Tan, Qiao-Cheng Qiu, Yuan-Hong Huang, Shuai-shuai Ge, Zi-Hao Wang, Jia Chen, Xiao-Wen Tang, De-Pei Wu, Sheng-Li Xue, Zheng Li, Hai-Ping Dai
Journal: Blood Cancer Journal (2023)
Automated Insulin Delivery Systems in Children and Adolescents With Type 1 Diabetes: A Systematic Review and Meta-analysis of Outpatient Randomized Controlled Trials
Authors: Baoqi Zeng, Le Gao, Qingqing Yang, Hao Jia, Feng Sun
Journal: Diabetes Care (2023)

BACKGROUND The glycemic control of automated insulin delivery (AID) systems in outpatient children and adolescents with type 1 diabetes (T1D) has not been systematically evaluated. PURPOSE To evaluate the efficacy and safety of AID systems in children and adolescents in outpatient settings. DATA SOURCES PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched until 4 May 2023. This study was registered with PROSPERO (2023, CRD42023395252). STUDY SELECTION Randomized controlled trials that compared AID systems with conventional insulin therapy in outpatient children and adolescents with T1D and reported continuous glucose monitoring outcomes were selected. DATA EXTRACTION Percent time in range (TIR) (3.9–10 mmol/L), time below range (TBR) (&amp;lt;3.9 mmol/L), and time above range (TAR) (&amp;gt;10 mmol/L) were extracted. Data were summarized as mean differences (MDs) with 95% CIs. DATA SYNTHESIS Twenty-five trials (1,345 participants) were included in the meta-analysis. AID systems were associated with an increased percentage of TIR (MD, 11.38% [95% CI 9.01–13.76], P &amp;lt; 0.001; high certainty). The favorable effect was consistent whether AID was used over 3 months (10.46% [8.71–12.20]) or 6 months (10.87% [7.11–14.63]). AID systems had a favorable effect on the proportion of TBR (−0.59% [−1.02 to −0.15], P = 0.008; low certainty) or TAR (−12.19% [−14.65 to −9.73], P &amp;lt; 0.001; high certainty) compared with control treatment. LIMITATIONS Substantial heterogeneity was observed in most analyses. CONCLUSIONS AID systems are more effective than conventional insulin therapy for children and adolescents with T1D in outpatient settings. The favorable effect is consistent both in the short term and long term.
Risk Factors Amenable to Primary Prevention of Type 2 Diabetes Among Disaggregated Racial and Ethnic Subgroups in the U.S.
Authors: Alain K. Koyama, Kai McKeever Bullard, Stephen Onufrak, Fang Xu, Ryan Saelee, Yoshihisa Miyamoto, Meda E. Pavkov
Journal: Diabetes Care (2023)

OBJECTIVE Race and ethnicity data disaggregated into detailed subgroups may reveal pronounced heterogeneity in diabetes risk factors. We therefore used disaggregated data to examine the prevalence of type 2 diabetes risk factors related to lifestyle behaviors and barriers to preventive care among adults in the U.S. RESEARCH DESIGN AND METHODS We conducted a pooled cross-sectional study of 3,437,640 adults aged ≥18 years in the U.S. without diagnosed diabetes from the Behavioral Risk Factor Surveillance System (2013–2021). For self-reported race and ethnicity, the following categories were included: Hispanic (Cuban, Mexican, Puerto Rican, Other Hispanic), non-Hispanic (NH) American Indian/Alaska Native, NH Asian (Chinese, Filipino, Indian, Japanese, Korean, Vietnamese, Other Asian), NH Black, NH Pacific Islander (Guamanian/Chamorro, Native Hawaiian, Samoan, Other Pacific Islander), NH White, NH Multiracial, NH Other. Risk factors included current smoking, hypertension, overweight or obesity, physical inactivity, being uninsured, not having a primary care doctor, health care cost concerns, and no physical exam in the past 12 months. RESULTS Prevalence of hypertension, lifestyle factors, and barriers to preventive care showed substantial heterogeneity among both aggregated, self-identified racial and ethnic groups and disaggregated subgroups. For example, the prevalence of overweight or obesity ranged from 50.8% (95% CI 49.1–52.5) among Chinese adults to 79.8% (73.5–84.9) among Samoan adults. Prevalence of being uninsured among Hispanic subgroups ranged from 11.4% (10.9–11.9) among Puerto Rican adults to 33.0% (32.5–33.5) among Mexican adults. CONCLUSIONS These findings underscore the importance of using disaggregated race and ethnicity data to accurately characterize disparities in type 2 diabetes risk factors and access to care.
Cardiac output drop reflects circulatory attrition after Fontan completion: serial cardiac magnetic resonance study
Authors: Sara C Arrigoni, Rolf M F Berger, Tjark Ebels, Douwe Postmus, Elke S Hoendermis, Paul H Schoof, Tineke P Willems, Joost P van Melle
Journal:  (2023)

Abstract Aims Cardiac magnetic resonance (CMR) imaging is a main diagnostic tool in the follow-up of Fontan patients. However, the value of serial CMR for the evaluation of Fontan attrition is unknown. The aim of this prospective study of serial CMR is to describe the analysis of time-dependent evolution of blood flow distribution, ventricular volumes, and function in patients after Fontan completion. Methods and results In this prospective single-centre study, between 2012 and 2022, 281 CMR examinations were performed in 88 Fontan patients with distribution of blood flows, measurements of ventricular volumes, and ejection fraction. Linear mixed model regression for repeated measurements was used to analyse changes of measurements across serial CMR examinations. During a time interval of 10 years, the median number of CMR per patient was 3 (range 1–5). Indexed flow of ascending aorta, caval veins, and pulmonary arteries decreased significantly across serial CMR examinations. Although a decrease of mean indexed aortic flow (3.03 ± 0.10 L/min/m2 at first CMR vs. 2.36 ± 0.14 L/min/m2 at fourth CMR, P &amp;lt; 0.001) was observed, ejection fraction did not decline (50 ± 1% at first CMR vs. 54 ± 2% at fourth CMR, P = 0.070). Indexed ventricular volumes did not differ significantly across serial CMR examinations. Conclusion The decrease of indexed aortic and cavopulmonary flows reflects the attrition of univentricular circulation and can be detected by means of serial CMR. Ventricular systolic dysfunction does not contribute significantly to this attrition. In order to detect significant change of indexed aortic flow, we recommend performing serial CMR as routine practice in the Fontan population.
ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases
Authors: Isabell Brikell, Honghui Yao, Lin Li, Aske Astrup, Le Gao, Malcolm B Gillies, Tian Xie, Yanli Zhang-James, Søren Dalsgaard, Anders Engeland, Stephen V Faraone, Jan Haavik, Catharina Hartman, Patrick Ip, Unnur Jakobsdóttir Smári, Henrik Larsson, Kenneth KC Man, Juliana de Oliveira Costa, Sallie-Anne Pearson, Nina Pil Hostrup Nielsen, Harold Snieder, Theresa Wimberley, Ian CK Wong, Le Zhang, Helga Zoega, Kari Klungsøyr, Zheng Chang
Journal: The Lancet Psychiatry (2023)
<i>Escherichia coli</i> triggers α-synuclein pathology in the <i>LRRK2</i> transgenic mouse model of PD
Authors: Dongxiao Liang, Han Liu, Ruoqi Jin, Renyi Feng, Jiuqi Wang, Chi Qin, Rui Zhang, Yongkang Chen, Jingwen Zhang, Junfang Teng, Beisha Tang, Xuebing Ding, Xuejing Wang
Journal: Gut Microbes (2023)

Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of LRRK2 risk variants are still unknown. Here, we report that a markedly increased abundance of Escherichia coli (E. coli) in the intestinal microbiota was detected in LRRK2 risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that E. coli administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in Lrrk2 R1628P mice, due to the co-occurrence of Lrrk2 variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in E. coli-derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in Lrrk2 R1628P mice. Our findings elaborate on the mechanism that E. coli triggers α-syn pathology in Lrrk2 R1628P mice, and highlight a novel gene-environment interaction pattern in LRRK2 risk variants. Even more importantly, the findings reveal the interplay between the specific risk gene and the matched environmental factors triggers the initiation of α-syn pathology in sPD.